Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(716)

Published: Oct. 4, 2023

Metabolic dysfunction–associated steatohepatitis (MASH) is a severe form of liver disease that poses global health threat because its potential to progress advanced fibrosis, leading cirrhosis and cancer. Recent advances in single-cell methodologies, refined models, genetic epigenetic insights have provided nuanced understanding MASH fibrogenesis, with substantial cellular heterogeneity livers providing potentially targetable cell-cell interactions behavior. Unlike mechanisms underlying fibrosis regression are still inadequately understood, although antifibrotic targets been recently identified. A treatment framework could lead noninvasive assessment targeted therapies preserve hepatocellular function restore the liver’s architectural integrity.

Language: Английский

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Molecular mechanisms in MASLD/MASH-related HCC

Hepatology, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 13, 2024

Liver cancer is the third leading cause of cancer-related deaths and ranks as sixth most prevalent type globally. NAFLD or metabolic dysfunction-associated steatotic liver disease, its more severe manifestation, NASH steatohepatitis (MASH), pose a significant global health concern, affecting approximately 20%-25% population. The increased prevalence disease MASH parallel to increasing rates obesity-associated diseases, including 2 diabetes, insulin resistance, fatty diseases. can progress MASH-related HCC (MASH-HCC) in about 2% cases each year, influenced by various factors such genetic mutations, carcinogen exposure, immune microenvironment, microbiome. MASH-HCC exhibits distinct molecular characteristics compared other causes affects both men women equally. management early intermediate-stage typically involves surgery locoregional therapies, while advanced treated with systemic anti-angiogenic therapies checkpoint inhibitors. In this comprehensive review, we consolidate previous research findings also providing current insights into intricate processes underlying development. We delve MASH-HCC-associated variations somatic progression models, multiomics analysis, immunological microenvironmental impacts, discuss targeted/combined overcome evasion biomarkers recognize treatment responders. By furthering our comprehension mechanisms MASH-HCC, goal catalyze advancement potent strategies, ultimately enhanced patient outcomes.

Language: Английский

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Vicious Cycle‐Breaking Lipid Nanoparticles Remodeling Multicellular Crosstalk to Reverse Liver Fibrosis

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(16)

Published: Jan. 9, 2024

During liver fibrogenesis, the reciprocal crosstalk among capillarized sinusoidal endothelial cells (LSECs), activated hepatic stellate (HSCs), and dysfunctional hepatocytes constructs a self-amplifying vicious cycle, greatly exacerbating disease condition weakening therapeutic effect. Limited by malignant cellular interactions, previous single-cell centric treatment approaches show unsatisfactory efficacy fail to meet clinical demand. Herein, cycle-breaking strategy is proposed target repair pathological separately terminate progression of fibrosis. Chondroitin sulfate-modified vismodegib-loaded nanoparticles (CS-NPs/VDG) are designed efficiently normalize fenestrae phenotype LSECs restore HSCs quiescent state inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid-modified silybin-loaded (GA-NPs/SIB) prepared function relieving oxidative stress. The results successful interruption cycle as well distinct fibrosis resolution in two animal models through multiregulation cells. This work not only highlights significance modulating but also provides promising avenue for developing antifibrotic regimens.

Language: Английский

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Hepatic Fibrosis and Cancer: The Silent Threats of Metabolic Syndrome

Diabetes & Metabolism Journal, Journal Year: 2024, Volume and Issue: 48(2), P. 161 - 169

Published: Jan. 26, 2024

Metabolic dysfunction-associated steatotic (fatty) liver disease (MASLD), previously termed non-alcoholic fatty disease, is a worldwide epidemic that can lead to hepatic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The typically component of the metabolic syndrome accompanies obesity, often overlooked because manifestations are clinically silent until late-stage present (i.e., cirrhosis). Moreover, Asian populations, including Koreans, have higher fraction patients who lean, yet their illness has same prognosis or worse than those obese. Nonetheless, ongoing injury inflammation ballooning hepatocytes as classic features. Over time, fibrosis develops following activation stellate cells, liver’s main fibrogenic cell type. usually more advanced in with type 2 diabetes mellitus, indicating all diabetic should be screened for disease. Although there been substantial progress clarifying pathways no approved therapies yet, but current research seeks uncover driving hopes identifying new therapeutic targets. Emerging molecular methods, especially single sequencing technologies, revolutionizing our ability clarify mechanisms underlying MASLD-associated HCC.

Language: Английский

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Spatial genomics: mapping human steatotic liver disease

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 21(9), P. 646 - 660

Published: April 23, 2024

Language: Английский

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AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion

Nature Biotechnology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Abstract Therapeutic efficacy and safety of adeno-associated virus (AAV) liver gene therapy depend on capsid choice. To predict AAV performance under near-clinical conditions, we established side-by-side comparison at single-cell resolution in human livers maintained by normothermic machine perfusion. AAV-LK03 transduced hepatocytes much more efficiently specifically than AAV5, AAV8 AAV6, which are most commonly used clinically, AAV-NP59, is better transducing engrafted immune-deficient mice. preferentially periportal normal liver, whereas AAV5 targeted pericentral steatotic liver. sinusoidal endothelial cells as hepatocytes. steatosis influenced vector episome formation, determines durability, with delaying concatemerization. Our findings inform choice clinical therapy, including consideration disease-relevant hepatocyte zonation effects steatosis, facilitate the development capsids that transduce or other therapeutically relevant cell types maximum efficiency specificity.

Language: Английский

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Integrative analysis identifies oxidative stress biomarkers in non-alcoholic fatty liver disease via machine learning and weighted gene co-expression network analysis

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 27, 2024

Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic globally, with potential to progress non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. Given absence of effective treatments halt its progression, novel molecular approaches NAFLD diagnosis treatment are paramount importance. Methods Firstly, we downloaded oxidative stress-related genes from GeneCards database retrieved NAFLD-related datasets GEO database. Using Limma R package WGCNA, identified differentially expressed closely associated NAFLD. In our study, 31 intersection by analyzing among genes, as through Weighted Gene Co-expression Network Analysis (WGCNA). a study between Oxidative Stress (OS), three hub using machine learning algorithms: Least Absolute Shrinkage Selection Operator (LASSO) regression, Support Vector Machine - Recursive Feature Elimination (SVM-RFE), RandomForest. Subsequently, nomogram was utilized predict incidence The CIBERSORT algorithm employed for immune infiltration analysis, single sample Set Enrichment (ssGSEA) functional enrichment Protein-Protein Interaction (PPI) networks explore relationships other intersecting OS. distribution these across six cell clusters determined single-cell RNA sequencing. Finally, utilizing relevant data Attie Lab Diabetes Database, tissues NASH mouse model, Western Blot (WB) Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) assays were conducted, this further validated significant roles CDKN1B TFAM in Results course research, strong association stress Subsequent analysis external validation pinpointed two genes: TFAM, demonstrating closest correlation Conclusion This investigation found that hold targets NAFLD, thereby offering innovative perspectives clinical management.

Language: Английский

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Single-cell and spatially resolved transcriptomics for liver biology

Hepatology, Journal Year: 2023, Volume and Issue: 80(3), P. 698 - 720

Published: April 1, 2023

Single-cell transcriptomics enables the identification of rare cell types and inference state transitions, whereas spatially resolved allows quantification cells genes in context tissues. The recent progress these new technologies is improving our understanding landscape its roles diseases. Here, we review key biological insights into liver homeostasis, development, regeneration, chronic disease, cancer obtained from single-cell transcriptomics. We highlight atlas that characterizes comprehensive cellular composition; diversity function; spatial architecture such as zonation, communication, proximity; identity conversion cell-specific alterations are associated with pathology; therapeutic targets. further discuss outstanding challenges, advanced experimental technologies, computational methods help to address challenges.

Language: Английский

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Hepatic fructose metabolism is antagonized by growth hormone/insulin-like growth factor signaling via regulation of ketohexokinase expression

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Overconsumption of added sugars such as fructose has been associated with a remarkable decline in metabolic health. Fructose is primarily metabolized by the small intestines and liver, via phosphorylation mediated ketohexokinase (KHK). KHK activity traditionally viewed lacking negative feedback mechanisms, those present to limit glucose metabolism, leading excessive fat accumulation characteristic dysfunction-associated liver disease (MASLD). In this study, we observe downregulation hepatocytes diet-induced genetic models MASLD. Reduced coincides decreased flux fructose-derived carbons into glycolytic amino acid pathways, suggesting presence mechanisms that KHK-mediated fructolysis liver. We subsequently focused on growth hormone (GH)/insulin-like factor (IGF) signaling pathway potential mechanism antagonizing expression. transgenic mice enhanced GH signaling, levels are reduced, whereas reduced leads increased Additionally, administration IGF-1 cell cultures induces time-dependent degradation KHK, facilitated direct interactions between receptor (IGF-1R). Single-nuclei RNA sequencing revealed elevated IGF-1R expression from MASLD mice, supported human patient samples, which also show Taken together, these findings describe novel GH/IGF-1 regulates offering new insights how adapts stress fructose-driven dysfunction.

Language: Английский

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Insight into the function of the Golgi membrane protein GOLM1 in cholangiocytes through interactomic analysis

FEBS Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

GOLM1, a Golgi membrane protein, is upregulated in cancers and liver diseases. Analysis of public RNAseq data from healthy human suggested that GOLM1 predominantly expressed cholangiocytes. Therefore, this study was initiated to understand the molecular functions cholangiocytes through protein interactomics. The findings reveal number putative GOLM1-interacting partners involved cellular regimes such as mitochondrial functions, ribonucleoprotein biogenesis, cell cycle, basement organization. Further, validate select key roles, silenced MMNK-1 effects on were studied. silencing resulted impaired function, reduced P-body markers, increased apoptosis, adhesion, suggesting crucial roles maintaining normal cholangiocyte metabolism function.

Language: Английский

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